Induction of arginase I and II in bleomycin-induced fibrosis of mouse lung

• Published in: American journal of physiology. Lung cellular and molecular physiology 2003-08, Vol.285 (2), p.313-L321
• Main Authors: Endo, Motoyoshi, Oyadomari, Seiichi, Terasaki, Yasuhiro, Takeya, Motohiro, Suga, Moritaka, Mori, Masataka, Gotoh, Tomomi
• Format: Article
• Language: English
• Subjects: Animals; Arginase - biosynthesis; Arginase - genetics; Arginine - metabolism; Bleomycin - toxicity; Gene Expression Regulation, Enzymologic - drug effects; Isoenzymes - biosynthesis; Isoenzymes - genetics; Lung - drug effects; Lung - enzymology; Male; Mice; Mice, Inbred C57BL; Pulmonary Fibrosis - chemically induced; Pulmonary Fibrosis - enzymology; Reference Values; RNA, Messenger - genetics; Transcription, Genetic - drug effects
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00434.2002

1 Department of Molecular Genetics, 2 First Department of Internal Medicine, and 3 Second Department of Pathology, Kumamoto University School of Medicine, Kumamoto 860-0811, Japan Submitted 17 December 2002 ; accepted in final form 31 March 2003 Arginase, which hydrolyzes arginine to urea and ornithine, is a precursor for the synthesis of polyamines and proline, which is abundant in collagen. The supply of proline can be a crucial factor in the process of lung fibrosis. We investigated the induction of arginine metabolic enzymes in bleomycin-induced mouse lung fibrosis. Histological studies and quantification of lung hydroxyproline showed that lung fibrosis develops in up to 14 days after bleomycin treatment. Under these conditions, collagen I mRNA was induced gradually in up to 15 days, and the content of hydroxyproline reached a maximum at 10 days. Arginase I mRNA was undetectable before bleomycin treatment but was induced 5–10 days after this treatment. Arginase I protein was induced at 7 days and remained little changed for up to 10 days and decreased at 14 days. On the other hand, arginase II mRNA that was detectable before treatment was increased gradually for up to 10 days and decreased at 14 days. Arginase II protein began to increase at day 5 , increased for up to 10 days, and was decreased at day 14 . mRNAs for cationic amino acid transporter-2 and ornithine decarboxylase were induced in a manner similar to that seen with collagen I mRNA. Immunohistochemical analysis showed that arginase I is induced in macrophages, whereas arginase II is induced in various cell types, including macrophages and myofibroblasts, and roughly colocalizes with the collagen-specific chaperone heat shock protein 47. Our findings suggest that arginine metabolic enzymes play an important role in the development of lung fibrosis, at least in mice. macrophage; lung fibrosis; arginine; collagen Address for reprint requests and other correspondence: T. Gotoh, Dept. of Molecular Genetics, Kumamoto Univ. School of Medicine, Honjo 2-2-1, Kumamoto 860-0811, Japan (E-mail: tomomi{at}gpo.kumamoto-u.ac.jp ).